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Publication numberUS8084612 B2
Publication typeGrant
Application numberUS 12/350,450
Publication dateDec 27, 2011
Filing dateJan 8, 2009
Priority dateJan 8, 2008
Also published asCA2711508A1, CA2711508C, CA2794054A1, CN101910126A, CN101910126B, EP2240443A1, EP2240443B1, EP2583963A1, US20090291947, WO2009087564A1
Publication number12350450, 350450, US 8084612 B2, US 8084612B2, US-B2-8084612, US8084612 B2, US8084612B2
InventorsBin Shao, Jiangchao Yao
Original AssigneePurdue Pharma L.P.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Proline analogs as ligands for cannabinoid receptors
US 8084612 B2
Abstract
The invention relates to compounds of Formulae I(a) to XI

and pharmaceutically acceptable salts and solvates thereof (Proline Analog Compounds), that are useful, e.g., as ligands for cannabinoid receptors, as compositions comprising a Proline Analog Compound and a pharmaceutically acceptable carrier, in methods of making such Proline Analog Compounds, and in methods for treating or preventing a Condition, such as pain, nausea, vomiting and an eating disorder, comprising administering an effective amount of a Proline Analog Compound to an animal in need thereof.
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Claims(32)
1. A compound of formula I(a):
or a pharmaceutically acceptable salt thereof, wherein:
X is S or O;
R1 is —(C1-C10 alkyl), —O(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,
R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with 1, 2, or 3 R3 groups;
each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
each halo is independently —F, —Cl, —Br, or —I;
k is an integer selected from the group consisting of 2, 3, and 4; and
each m is independently an integer selected from the group consisting of 0, 1, 2, 3, and 4.
2. A compound of formula III(a):
or a pharmaceutically acceptable salt thereof, wherein:
X is S or O;
R1 is —(C1-C10 alkyl), —O(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,
R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with 1, 2, or 3 R3 groups;
each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
each halo is independently —F, —Cl, —Br, or —I;
n is an integer selected from the group consisting of 0, 1, 2, 3, and 4; and
each m is independently an integer selected from the group consisting of 0, 1, 2, 3, and 4.
3. A compound of formula I(b) or formula III(b):
or a pharmaceutically acceptable salt thereof, wherein:
X is S or O;
R1 is —(C1-C10 alkyl), —O(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,
R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with 1, 2, or 3 R3 groups;
each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1—C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
each halo is independently —F, —Cl, —Br, or —I;
n is an integer selected from the group consisting of 0, 1, 2, 3, and 4; and
each m is independently is an integer selected from the group consisting of 0, 1, 2, 3, and 4.
4. The compound of any one of claims 1, 2, and 3, wherein R1 is —O(CH2CH3).
5. The compound of any one of claims 1, 2, and 3, wherein R1 is
6. The compound of claim 2 or 3, wherein n is 2.
7. A compound of formula I(a):
or a pharmaceutically acceptable salt thereof, wherein:
X is S or O;
R1 is —(C1-C10 alkyl), —O(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,
R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with 1, 2, or 3 R3 groups;
each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2,
each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
each halo is independently —F, —Cl, —Br, or —I;
k is 2; and
each m is independently an integer selected from the group consisting of 0, 1, 2, 3, and 4.
8. The compound of any one of claims 1, 2, and 3, wherein each m is 0.
9. The compound of any one of claims 1, 2, and 3, wherein R2 is
10. The compound of any one of claims 1, 2, and 3, wherein R2 is
11. The compound of any one of claims 1, 2, and 3, wherein R2 is
12. The compound of any one of claims 1, 2, and 3, wherein R2 is
13. The compound of any one of claims 1, 2, and 3, wherein R2 is
14. The compound of any one of claims 1, 2, and 3, wherein R2 is
15. A compound of claim 7 selected from:
and pharmaceutically acceptable salts thereof.
16. The compound of any one of claims 1, 2, and 3, wherein X is S.
17. The compound of any one of claims 1, 2, and 3, wherein X is O.
18. A composition comprising a compound of any one of claims 1, 2, 3, and 7, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
19. A compound of claim 1 which is
or a pharmaceutically acceptable salt thereof.
20. A compound of claim 2 which is
or a pharmaceutically acceptable salt thereof.
21. The compound of any one of claims 1, 2, and 3, wherein R1 is
wherein m is 1 and R4 is -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl).
22. The compound of claim 21, wherein R4 is —OH or —O(C1-C4 alkyl), and R5 is —(C1-C10 alkyl), —CH2NH(C1-C4 alkyl), or —CH2N(C1-C4 alkyl)2.
23. The compound of any one of claims 1, 2, and 3, wherein R1 is
24. The compound of claim 23, wherein R1 is
25. The compound of any one of claims 1, 2, and 3, wherein R1 is —(C1-C10 alkyl), —O(C1-C10 alkyl), —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2.
26. The compound of claim 25, wherein R1 is —(C1-C10 alkyl).
27. The compound of claim 26, wherein R1 is —(C1-C4 alkyl).
28. The compound of any one of claims 1, 2, and 3, wherein R2 is
29. The compound of claim 28, wherein R2 is
30. The compound of any one of claims 1, 2, and 3, wherein R2 is —(C1-C10 alkyl).
31. The compound of claim 30, wherein R1 is —(C1-C4 alkyl).
32. A kit comprising a container containing a compound or a pharmaceutically acceptable salt of a compound of any one of claims 1, 2, 3, and 7.
Description
1. CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 61/010,447, filed on Jan. 8, 2008, the contents of which are incorporated herein by reference.

2. FIELD OF THE INVENTION

The present invention relates to Proline Analog Compounds that are ligands for cannabinoid receptors, compositions comprising a Proline Analog Compound and a pharmaceutically-acceptable carrier, methods of making such Proline Analog Compounds, and methods for treating or preventing a Condition comprising administering an effective amount of a Proline Analog Compound to an animal in need thereof.

3. BACKGROUND OF THE INVENTION

Cannabinoid receptors belong to the G-protein coupled (“GPCR”) receptor superfamily. Cannabinoid receptors include at least two subtypes, referred to as CB1 and CB2, which are distinguished by their amino acid sequence, tissue distribution, signaling mechanisms, and ability to bind subtype-specific ligands. CB1 receptors are found in the central and peripheral nervous systems, while CB2 receptors are primarily expressed by cells of the immune system (Howlett (2002) Prostaglandins and other Lipid Mediators (68-69): 619-631; Pertwee et al. (2002) Prostaglandins, Leukotrienes and Essential Fatty Acids 66(2&3): 101-121; Piomelli (2003) Nature Reviews (Neuroscience) 4: 873-884.

Agonist binding to CB1 and CB2 receptors initiates signals that are transduced via Gi/o proteins coupled to the cannabinoid receptors. The transduced signals lead to inhibition of stimulus-induced adenylate cyclase, inhibition of cAMP/protein Innase A-mediated effects, and stimulation of mitogen-activated protein kinase. Agonist binding to CB1 receptors also inhibits voltage-gated Ca+2 channels and stimulates inwardly-rectifying K+ channels (Mackie et al. (1995) J. Neurosci 15(10): 6552-61). Stimulation of presynaptic CB1 receptors by agonist binding has been reported to inhibit neurotransmitter release in both the central and peripheral nervous systems (Howlett (2002) Pharmacol. Rev. 54(2): 161-202; Pertwee et al. (2002) Prostaglandins, Leukotrienes and Essential Fatty Acids 66(2&3): 101-121).

Cannabinoid receptor ligands can be characterized by both their selectivity (e.g. binding strength to cannabinoid receptors) and their specificity (e.g. relative binding strength to a CB1 receptor as compared to a CB2 receptor). Moreover, cannabinoid receptor ligands may be characterized as agonists, antagonists or inverse agonists of the receptor to which they bind. Accordingly, specific cannabinoid receptor ligands can induce profoundly different biochemical and physiological effects and, therefore, will have different therapeutic applications, as evident from the abbreviated list provided below.

For example, cannabinoids have been described as useful for the treatment of nausea and vomiting associated with administration of anti-neoplastic agents to cancer patients (Bagshaw (2002) J. Palliative Care 18(2): 111-122; Grotenhermen (2004) Neuroendocrinol. Lett. 25(1/2): 1423).

The cannabinoid system has also been reported to be directly involved in the regulation of physiological processes central to the control of appetite and body weight. Administration of cannabinoid receptor agonists has been shown to stimulate the appetite of HIV/AIDS patients afflicted with anorexia and cachexia. Administration of cannabinoid receptor antagonists/inverse agonists has been described as appetite depressants useful for the treatment and prevention of obesity (Lange et al. (2004) Curr. Opin. Drug Disc. & Devel. 7(4): 498-506; Black (2004) Curr. Opin. Investig. Drugs 5(4): 389-94; Fernandez et al. (2004) Curr. Opin. Investig. Drugs 5(4): 430-435). For example, administration of the CB1 receptor antagonist (SR 141716A) has been reported to induce a reduction in body weight and adiposity in rodents.

Cannabinoids have also been reported to be therapeutically-useful for the treatment of diseases characterized by muscle spasticity, spasm, or tremor. In particular, cannabinoids have been reported as capable of alleviating the spasticity associated with spinal cord injury and multiple sclerosis, as well as movement disorders associated with Tourette's syndrome and L-dopa-induced dyskenesia of Parkinson's disease (Grotenhermen (2004) Neuroendocrinol. Lett. 25(1/2): 14-23; Croxford (2003) CNS Drugs 17(3): 179-202).

Cannabinoid receptor agonists have been reported to attenuate pain in vivo and therefore are potentially useful for the alleviation of acute and chronic pain (Ahmad et al. (2004) Curr. Opin. Invest. Drugs 5(1): 67-70; Cichewicz (2004) Life Sciences 74: 1317-24; Walker et al. (2002) Pharmacol. Therapeut. 95: 127-135).

Cannabinoids have been reported to lower intraocular pressure, apparently via binding to intraocular CB1 receptors. Accordingly, it has been suggested in the art that such ligands may be useful for the prevention and treatment of glaucoma (Tomida et al. (2003) Br. J. Opthamol 88: 708-713). The term “glaucoma” comprises a set of diseases of the eye involving injury to the optic nerve. In certain instances, increased pressure within the eye leads to mechanical compression of and/or inhibition of blood flow to the optic nerve. The final stage of visual loss involves selective apoptosis of retinal ganglion cells as a result of compressive and/or ischemic injury to axons at the optical disc (Tomida et al. (2003) Br. J. Opthamol 88: 708-71).

Pruritus (an unpleasant sensation that prompts scratching) has been treated by phototherapy with ultraviolet B or PUVA (administration of psoralen followed by exposure of the target tissue to long-wavelength ultraviolet light), and with therapeutic agents such as naltrexone, nalmefene, danazol, and tricyclic antidepressants. More recently, administration of the cannabinoid Δ9-tetrahydrocannabinol (“Δ9-THC”) has been reported to result in a decrease in pruritus in patients who had not responded to conventional treatments (Neff et al. (2002) Am. J. Gastroenterol. 97(8): 2117-2119).

Citation of any reference in Section 2 of this application is not intended as an admission that such reference is prior art to the present application.

4. SUMMARY OF THE INVENTION

The present invention encompasses compounds of Formula I(a):


and pharmaceutically acceptable salts and solvates thereof, wherein:

  • X is S or O;
  • R1 is —(C3-C10 alkyl), —O(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,

  • R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with one, two, or three R3 groups;
  • each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
  • each R4 is independently -halo, —C(halo)3, —CH2(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
  • R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
  • each halo is independently —F, —Cl, —Br, or —I;
  • k is an integer selected from the group consisting of 2, 3, and 4; and
  • each m is independently an integer selected from the group consisting of 0, 1, 2, 3, and 4.

The present invention further encompasses compounds of formula I(b):


and pharmaceutically acceptable salts and solvates thereof, wherein:

  • X is S or O;
  • R1 is —(C1-C10 alkyl), —O(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,

  • R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with one, two, or three R3 groups;
  • each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
  • each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
  • R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
  • each halo is independently —F, —Cl, —Br, or —I;
  • n is an integer selected from the group consisting of 0, 1, 2, 3, and 4; and
  • each m is independently an integer selected from the group consisting of 0, 1, 2, 3, and 4.

The present invention further encompasses compounds of formula III(a):


and pharmaceutically acceptable salts and solvates thereof, wherein:

  • X is S or O;
  • R1 is —(C1-C10 alkyl), —O(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,

  • R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with one, two, or three R3 groups;
  • each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
  • each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
  • R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(CO1C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
  • each halo is independently —F, —Cl, —Br, or —I;
  • n is an integer selected from the group consisting of 0, 1, 2, 3, and 4; and
  • each m is independently an integer selected from the group consisting of 0, 1, 2, 3, and 4.

The present invention further encompasses compounds of formula III(b):


and pharmaceutically acceptable salts and solvates thereof, wherein:

  • X is S or O;
  • R1 is —(C1-C10 alkyl), —O(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,

  • R2 is —(C1-C10 aryl), —(C3-C10) cycloakyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with one, two, or three R3 groups;
  • each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
  • each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
  • R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
  • each halo is independently —F, —Cl, —Br, or —I;
  • n is an integer selected from the group consisting of 0, 1, 2, 3, and 4; and
  • each m is independently is an integer selected from the group consisting of 0, 1, 2, 3, and 4.

The present invention further encompasses compounds having the formula II(a):


and pharmaceutically acceptable salts and solvates thereof, wherein:

  • X is S or O;
  • R9 is —(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,

  • R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with one, two, or three R3 groups;
  • each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
  • each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
  • R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
  • wherein each R6 and R7 is independently H, —(C1-C10 alkyl), —CH2O(C1-C4 alkyl), —CH2NH(C1-C4 alkyl), —CH2N(C1-C4 alkyl)2, —(C3-C8)cycloalkyl either unsubstituted or substituted with one, two, or three R3 groups, phenyl either unsubstituted or substituted with one, two, or three R3 groups, or -(5 to 7 membered)heteroaryl either unsubstituted or substituted with one to three R3 groups, or R6 and R7 taken together with the carbon atoms to which they are attached form a -(5 to 7 membered)heteroaryl ring optionally substituted with one, two, or three R3 groups or R6 and R7 taken together with the carbon atoms to which they are attached form an aromatic six-membered carbocyclic ring optionally substituted with one, two, or three R3 groups;
  • each halo is independently —F, —Cl, —Br, or —I; and
  • m is an integer selected from the group consisting of 0, 1, 2, 3, and 4.

The present invention further encompasses compounds of formula II(b):


and pharmaceutically acceptable salts and solvates thereof, wherein:

  • X is S or O;
  • R1 is —(C1-C10 alkyl), —O(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,

  • R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with one, two, or three R3 groups;
  • each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
  • each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
  • R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl)7 or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
  • each halo is independently —F, —Cl, —Br, or —I;
  • wherein each R6 and R7 is independently H, —(C1-C10 alkyl), —CH2O(C1-C4 alkyl), —CH2NH(C1-C4 alkyl), —CH2N(C1-C4 alkyl)2, —(C3-C8)cycloalkyl either unsubstituted or substituted with one to three R3 groups, phenyl either unsubstituted or substituted with one, two, or three R3 groups, or -(5 to 7 membered)heteroaryl either unsubstituted or substituted with one, two, or three R3 groups, or R6 and R7 taken together with the carbon atoms to which they are attached form a -(5 to 7 membered)heteroaryl ring optionally substituted with one to three R3 groups or R6 and R7 taken together with the carbon atoms to which they are attached form an aromatic six-membered carbocyclic ring optionally substituted with one to three R3 groups; and
  • m is an integer selected from the group consisting of 0, 1, 2, 3, and 4.

The present invention further encompasses compounds of formula X:


or a pharmaceutically acceptable salt or solvate thereof, wherein:

  • R9 is —(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,

  • R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with one, two, or three R3 groups;
  • each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
  • each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
  • R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
  • each halo is independently —F, —Cl, —Br, or —I; and
  • each m is independently an integer selected from the group consisting of 0, 1, 2, 3, and 4.

The present invention further encompasses compounds of formula XI:


or a pharmaceutically acceptable salt or solvate thereof, wherein:

  • R9 is —(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,

  • R2 is —(C1-C10 alkyl), —(C3-C8) cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl, or -(5 to 7 membered) heteroaryl, each being unsubstituted or substituted with one, two, or three R3 groups;
  • each R3 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, —NO2, —NH2, —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2, —(C1-C10 alkyl), —O(C1-C4 alkyl), —CONH2, —CONH(C1-C4 alkyl), or —CON(C1-C4 alkyl)2;
  • each R4 is independently -halo, —C(halo)3, —CH(halo)2, —CH2(halo), —OH, —(C1-C4 alkyl), or —O(C1-C4 alkyl);
  • R5 is —H, —C(halo)3, —CH(halo)2, —CH2(halo), —(C1-C10 alkyl), —(CH2)rO(C1-C4 alkyl), —(CH2)rNH(C1-C4 alkyl), or —(CH2)rN(C1-C4 alkyl)2, where r is an integer selected from the group consisting of 1, 2, 3, and 4;
  • each halo is independently —F, —Cl, —Br, or —I;
  • wherein each R6 and R7 is independently H, —(C1-C10 alkyl), —CH2O(C1-C4 alkyl), —CH2NH(C1-C4 alkyl), —CH2N(C1-C4 alkyl)2, —(C3-C8)cycloalkyl either unsubstituted or substituted with one to three R3 groups, phenyl either unsubstituted or substituted with one, two, or three R3 groups, or -(5 to 7 membered)heteroaryl either unsubstituted or substituted with one, two, or tree R3 groups, or R6 and R7 taken together with the carbon atoms to which they are attached form a -(5 to 7 membered)heteroaryl ring optionally substituted with one to three R3 groups or R6 and R7 taken together with the carbon atoms to which they are attached form an aromatic six-membered carbocyclic ring optionally substituted with one, two, or three R3 groups;
  • p is an integer selected from the group consisting of 0, 1, 2, 3, and 4; and
  • m is an integer selected from the group consisting of 0, 1, 2, 3, and 4.

In another embodiment the present invention also encompasses compounds of Formula II(a) and compounds of Formula II(b):


and pharmaceutically acceptable salts and solvates thereof, wherein X, R1, R2, R3, R4, R5, m, and halo are as above,

  • wherein each R6 and R7 is independently H, —(C1-C10 alkyl), —CH2O(C1-C4 alkyl), —CH2NH(C1-C4 alkyl), —CH2N(C1-C4 alkyl)2, —(C3-C8)cycloalkyl either unsubstituted or substituted with one, two, or three R3 groups, phenyl either unsubstituted or substituted with one, two, or three R3 groups, or -(5 to 7 membered)heteroaryl either unsubstituted or substituted with one, two, or three R3 groups, or R6 and R7 taken together with the carbon atoms to which they are attached form a -(5 to 7 membered)heteroaryl ring optionally substituted with one, two, or three R3 groups or R6 and R7 taken together with the carbon atoms to which they are attached form an aromatic six-membered carbocyclic ring optionally substituted with one, two, or three R3 groups; and
  • wherein R9 is —(C1-C10 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)2,

In another embodiment the present invention further encompasses compounds of Formula III(a) and compounds of Formula III(b):


and pharmaceutically acceptable salts and solvates thereof, wherein X, R1, R2, R3, R4, R5, m, n, and halo are as defined above.

Thus, the present invention encompasses compounds of Formula IV(a) and compounds of Formula V(a), as well as compounds of Formula IV(b) and compounds of Formula V(b):


and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, R4, R5, k, m, n, and halo are as defined.

Similarly, the present invention also encompasses compounds of Formula VI(a) and compounds of Formula VII(a), as well as compounds of Formula VI(b) and compounds of Formula VII(b):


and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, R4, R5, R6, R7, R9, m, and halo are as defined above.

The present invention farmer encompasses compounds of Formula VIII(a) and compounds of Formula IX(a), as well as compounds of Formula VIII(b) and compounds of Formula IX(b):


and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, R4, R5, m, n, and halo are as defined above.

The present invention fixer encompasses compounds of formula X:


and pharmaceutically acceptable salts and solvates thereof, wherein R2, R3, R4, R5, R9, m, and halo are as defined above.

The present invention also encompasses compounds of formula XI:


and pharmaceutically acceptable salts and solvates thereof, wherein p is an integer selected from the group consisting of 1, 2, 3, and 4, and wherein R2, R3, R4, R5, R6, R7, R9, m, and halo are as defined above.

A compound of Formula I(a), I(b), II(a), II(b), I(a), III(b), IV(a), IV(b), V(a), V(b), VI(a), VI(h), VI(a), VII(b), VII(a), VIII(b), IX(a), IX(b), X, or XI, or a pharmaceutically acceptable salt or solvate thereof (each being a “Proline Analog Compound”) is a cannabinoid receptor ligand useful for the treatment or prevention of a Condition in an animal, said condition defined below, and being treatable by modulation of an activity of a cannabinoid receptor.

In certain embodiments, the Proline Analog Compounds of the present invention are modulators of cannabinoid receptor function. In one aspect of this embodiment, a Proline Analog Compound of the present invention is a modulator of both CB1 receptor function and CB2 receptor function. In another aspect of this embodiment, a Proline Analog Compound of the present invention is a selective modulator of CB1 receptor function. In a further aspect of this embodiment, a Proline Analog Compound of the present invention is a selective modulator of CB2 receptor function. In another embodiment, a Proline Analog Compound is an agonist of a human CB1 receptor and a human CB2 receptor. In a further embodiment, a Proline Analog Compound is an antagonist or inverse agonist of a human CB1 receptor and a human CB2 receptor.

In still another embodiment, a Proline Analog Compound is an agonist of a human CB1 receptor. In a further embodiment, a Proline Analog Compound is an antagonist or inverse agonist of a human CB1 receptor.

In a still further embodiment, a Proline Analog Compound is an agonist of a human CB2 receptor. In a further embodiment, a Proline Analog Compound is an antagonist or inverse agonist of a human CB2 receptor.

The invention relates to compositions comprising a Proline Analog Compound, particularly an effective amount of a Proline Analog Compound, and a pharmaceutically acceptable carrier or excipient. The present compositions are useful for treating or preventing a Condition in an animal.

The present invention also encompasses a method of treating a Condition in an animal, comprising administering to an animal in need thereof, an effective amount of a Proline Analog Compound that is a modulator of one or more cannabinoid receptor functions.

The invention further relates to methods for preventing a Condition in an animal, comprising administering to an animal in need thereof an effective amount of a Proline Analog Compound.

The invention further relates to kits comprising a container containing an effective amount of a Proline Analog Compound and instructions for using it to treat or prevent a Condition in an animal.

The invention further relates to methods for modulating cannabinoid-receptor function in a cell, comprising contacting a cell capable of expressing a cannabinoid receptor with a Proline Analog Compound.

The invention further relates to methods for stimulating cannabinoid-receptor function in a cell, comprising contacting a cell expressing a cannabinoid receptor with a Proline Analog Compound capable of stimulating said cannabinoid receptor function.

The invention further relates to methods for inhibiting cannabinoid-receptor function in a cell, comprising contacting a cell expressing a cannabinoid receptor with a Proline Analog Compound capable of inhibiting said cannabinoid receptor function.

The invention further relates to use of a Proline Analog Compound for manufacturing a medicament useful for treating a Condition in an animal.

The invention further relates to methods for preparing a pharmaceutical composition, comprising the step of admixing a Proline Analog Compound and a pharmaceutically-acceptable carrier or excipient.

The present invention may be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.

5. DETAILED DESCRIPTION OF THE INVENTION 5.1 Definitions

As used herein, the following terms have the indicated meaning:

“—C1-C3 alkyl” means a straight or branched, non-cyclic, hydrocarbon chain having from 1 to 3 carbon atoms. Representative straight chain and branched chain —C1-C3 alkyls include -methyl, -ethyl, -n-propyl and isopropyl.

“—C1-C4 alkyl” means a straight or branched, non-cyclic, hydrocarbon chain having from 1 to 4 carbon atoms. Representative straight chain —C1-C4 alkyls include methyl, -ethyl, -n-propyl, and -n-butyl. Representative branched chain —C1-C4 alkyls include -isopropyl, -sec-butyl, -isobutyl, and -tert-butyl.

“Lower alkyl,” as used herein, means a straight or branched, non-cyclic, hydrocarbon chain having from 1 to 5 carbon atoms. Representative lower alkyl groups include methyl, ethyl, -n-propyl, -n-butyl, and -n-pentyl, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -2-methylbutyl, and -2,2-dimethylpropyl.

“—C1-C6 alkyl” means a straight or branched, non-cyclic, hydrocarbon chain having from 1 to 6 carbon atoms. Representative straight chain —C1-C6 alkyls include methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl. Representative branched chain —C1-C6 alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylbutyl.

“—(C1-C10)alkyl” means a straight chain or branched, non-cyclic, hydrocarbon having from 1 to 10 carbon atoms. Representative straight chain —(C1-C10) alkyls include methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl. Representative branched —(C1-C10) alkyls include isopropyl, sec-butyl, isobutyl, -tert-butyl, isopentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl.

“—C3-C8 cycloalkyl” means a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms. Representative —C3-C8 cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and -cyclooctyl.

“-(5- to 7-membered)heteroaryl” means a monocyclic aromatic heterocycle ring of 5 to 7 members, wherein at least one carbon atom of the ring is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. The -(5- to 7-membered)heteroaryl's ring contains at least one carbon atom. Representative -(5- to 7-membered)heteroaryls include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl, a tetrazolyl.

“CH2 (halo)” means a methyl group wherein one of the hydrogens of the methyl group has been replaced with a halogen. Representative —CH2(halo) groups include —CHF, —CH2Cl, —CH2Br, and —CH2I.

“CH(halo)2” means a methyl group wherein two of the hydrogens of the methyl group has been replaced with a halogen. Representative —CH(halo)2 groups include —CHF2, —CHCl2, —CHBr2, and —CHI2.

“C(halo)3” means a methyl group wherein each of the hydrogens of the methyl group has been replaced with a halogen. Representative —C(halo)3 groups include —CF3, —CCl3, —CBr3, and —CI3.

“-Halogen” or “halo” means —F, —Cl, —Br, or —I.

The term “animal,” includes, but is not limited to, a cow, ape, monkey, chimpanzee, baboon, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human.

The term “solvate” means a compound formed by salvation, i.e. the combination of solvent molecules with molecules or ions of a solute. In specific embodiments, a solvate of a Proline Analog compound of the invention a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone. In a specific embodiment, the solvate is a hydrate.

The term “stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers). Some Proline Analog compounds disclosed herein can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention is meant to encompass all such possible forms as well as the racemic and resolved forms and mixtures thereof. When the Proline Analog compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well. Thus, all stereoisomers (including but not limited to geometric isomers, optical isomers and the like) of the Proline Analog compounds of the invention (including those of the salts, solvates of the Proline Analog compounds, such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated to be within the scope of this invention.

The phrase “pharmaceutically acceptable salt,” as used herein, includes a salt formed from an acid and the basic nitrogen group of a Proline Analog Compound. Illustrative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term “pharmaceutically acceptable salt” also includes a salt of a Proline Analog Compound having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Illustrative bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia; and organic amines, such as unsubstituted or hydroxy substituted mono-, di-, or trialkylamines; dicyclohexylamine, tributylamine; pyridine; N-methyl-N-ethylamine; diethylamine; triethylamine; mono-, bis- or tris-(2-hydroxy-lower alkyl amines), such as mono- bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N, N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.

The terms “treat,” “treatment of” and “treating” a Condition include the lessening of the severity, the cessation, or the reversal of the symptoms of the Condition. In one illustrative embodiment, “treat,” “treating” or “treatment of” includes decreasing the overall frequency of episodes of pain.

The terms “prevent,” “prevention of” and “preventing” of a Condition include the avoidance of the onset of that Condition.

The terms “a” and “an” refer to one or more.

The phrase “cannabinoid receptor” means a CB1 receptor, or a CB2 receptor.

The phrase “effective amount” when used in connection with a Proline Analog Compound means an amount of the Proline Analog Compound that is useful for treating or preventing a Condition in an animal, or that can modulate, stimulate, or inhibit a cannabinoid receptor function in a cell.

The phrase “effective amount” when used in connection with another therapeutic agent means an amount for providing the therapeutic effect of that therapeutic agent when administered to an animal.

The phrase “modulator of a cannabinoid receptor” refers to a compound, e.g. a Proline Analog Compound, that activates or inhibits a cannabinoid receptor. A Proline Analog Compound, which is a ligand of a cannabinoid receptor, can modulate the activity of the cannabiniod receptor by acting as an agonist, partial agonist, inverse agonist, antagonist, or partial antagonist of that cannabinoid receptor.

The phrase “cannabinoid receptor agonist,” as used hereinafter, is meant to include compounds acting as full agonists or partial agonists.

The phrase “cannabinoid receptor antagonist,” as used hereinafter, is meant to include compounds acting as full antagonists, partial antagonists, or as inverse agonists of a cannabinoid receptor.

As used herein, a compound that binds to a receptor and mimics the regulatory effect(s) of an endogenous ligand is defined as an “agonist”. As used herein, a compound that binds to a receptor and is only partly effective as an agonist is defined as a “partial agonist”. As used herein, a compound that binds to a receptor but produces no regulatory effect, but rather blocks binding of another agent to the receptor is defined as an “antagonst”. (See Ross and Kenaidn, Pharmacodynamics: Mechanisms of Drug Action and the Relationship Between Drug Concentration and Effect, Chapter 2 in Goodman & Gilman's The Pharmacological Basis of Therapeutics 31-32 (J. G. Hardman, L. E. Limbird and A. Goodman-Gilman eds., 10th ed 2001). The phrase “inverse agonist” as used hereinafter, is meant to include compounds that bind to the receptor and stabilize the receptor in its inactive conformation. When a first group is “substituted with one or more” second groups, each of one or more of the first group's hydrogen atoms is replaced with a second group.

In one embodiment, a first group is substituted with up to three independently selected second groups.

In another embodiment, a first group is substituted with one or two independently selected second groups.

In another embodiment, a first group is substituted with only one second group.

5.2 The Proline Analog Compounds

Illustrative Proline Analog Compounds of Formula I(a) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 1
Compound
No.: R1 R2
AAA ((a) and (b))
AAB ((a) and (b))
AAC ((a) and (b))
AAD ((a) and (b))
AAE ((a) and (b))
AAF ((a) and (b))
AAG ((a) and (b))
AAH ((a) and (b))
AAI ((a) and (b))
AAJ ((a) and (b))
AAK ((a) and (b))
AAL ((a) and (b))
AAM ((a) and (b))
AAN ((a) and (b))
AAO ((a) and (b))
AAP ((a) and (b))
AAQ ((a) and (b))
AAR ((a) and (b))
AAS ((a) and (b))
AAT ((a) and (b))
AAU ((a) and (b))
AAV ((a) and (b))
AAW ((a) and (b))
AAX ((a) and (b))
AAY ((a) and (b))
AAZ ((a) and (b))
ABA ((a) and (b))
ABB ((a) and (b))
ABC ((a) and (b))
ABD ((a) and (b))
ABE ((a) and (b))
ABF ((a) and (b))
ABG ((a) and (b))
ABH ((a) and (b))
ABI ((a) and (b))
ABJ ((a) and (b))

Additional, illustrative Proline Analog Compounds of Formula I(b) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 2
Compound
No.: R1 R2
BAA ((a) and (b))
BAB ((a) and (b))
BAC ((a) and (b))
BAD ((a) and (b))
BAE ((a) and (b))
BAF ((a) and (b))
BAG ((a) and (b))
BAH ((a) and (b))
BAI ((a) and (b))
BAJ ((a) and (b))
BAK ((a) and (b))
BAL ((a) and (b))
BAM ((a) and (b))
BAN ((a) and (b))
BAO ((a) and (b))
BAP ((a) and (b))
BAQ ((a) and (b))
BAR ((a) and (b))
BAS ((a) and (b))
BAT ((a) and (b))
BAU ((a) and (b))
BAV ((a) and (b))
BAW ((a) and (b))
BAX ((a) and (b))
BAY ((a) and (b))
BAZ ((a) and (b))
BBA ((a) and (b))
BBB ((a) and (b))
BBC ((a) and (b))
BBD ((a) and (b))
BBE ((a) and (b))
BBF ((a) and (b))
BBG ((a) and (b))
BBH ((a) and (b))
BBI ((a) and (b))
BBJ ((a) and (b))

Illustrative Proline Analog Compounds of Formula II(a) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R9 and R2 are as follows:

TABLE 3
Compound
No.: R9 R2
CAA ((a) and (b))
CAB ((a) and (b))
CAC ((a) and (b))
CAD ((a) and (b))
CAE ((a) and (b))
CAF ((a) and (b))
CAG ((a) and (b))
CAH ((a) and (b))
CAI ((a) and (b))
CAJ ((a) and (b))
CAK ((a) and (b))
CAL ((a) and (b))
CAM ((a) and (b))
CAN ((a) and (b))
CAO ((a) and (b))
CAP ((a) and (b))
CAQ ((a) and (b))
CAR ((a) and (b))
CAS ((a) and (b))
CAT ((a) and (b))
CAU ((a) and (b))
CAV ((a) and (b))
CAW ((a) and (b))
CAX ((a) and (b))
CAY ((a) and (b))
CAZ ((a) and (b))
CBA ((a) and (b))
CBB ((a) and (b))
CBC ((a) and (b))
CBD ((a) and (b))

Additional, illustrative Proline Analog Compounds of Formula II(b) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 4
Compound No.: R1 R2
DAA ((a) and (b))
DAB ((a) and (b))
DAC ((a) and (b))
DAD ((a) and (b))
DAE ((a) and (b))
DAF ((a) and (b))
DAG ((a) and (b))
DAH ((a) and (b))
DAI ((a) and (b))
DAJ ((a) and (b))
DAK ((a) and (b))
DAL ((a) and (b))
DAM ((a) and (b))
DAN ((a) and (b))
DAO ((a) and (b))
DAP ((a) and (b))
DAQ ((a) and (b))
DAR ((a) and (b))
DAS ((a) and (b))
DAT ((a) and (b))
DAU ((a) and (b))
DAV ((a) and (b))
DAW ((a) and (b))
DAX ((a) and (b))
DAY ((a) and (b))
DAZ ((a) and (b))
DBA ((a) and (b))
DBB ((a) and (b))
DBC ((a) and (b))
DBD ((a) and (b))
DBE ((a) and (b))
DBF ((a) and (b))
DBG ((a) and (b))
DBH ((a) and (b))
DBI ((a) and (b))
DBJ ((a) and (b))

Illustrative Proline Analog Compounds of Formula III(a) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 5
Compound No.: R1 R2
EAA ((a) and (b))
EAB ((a) and (b))
EAC ((a) and (b))
EAD ((a) and (b))
EAE ((a) and (b))
EAF ((a) and (b))
EAG ((a) and (b))
EAH ((a) and (b))
EAI ((a) and (b))
EAJ ((a) and (b))
EAK ((a) and (b))
EAL ((a) and (b))
EAM ((a) and (b))
EAN ((a) and (b))
EAO ((a) and (b))
EAP ((a) and (b))
EAQ ((a) and (b))
EAR ((a) and (b))
EAS ((a) and (b))
EAT ((a) and (b))
EAU ((a) and (b))
EAV ((a) and (b))
EAW ((a) and (b))
EAX ((a) and (b))
EAY ((a) and (b))
EAZ ((a) and (b))
EBA ((a) and (b))
EBB ((a) and (b))
EBC ((a) and (b))
EBD ((a) and (b))
EBE ((a) and (b))
EBF ((a) and (b))
EBG ((a) and (b))
EBH ((a) and (b))
EBI ((a) and (b))
EBJ ((a) and (b))

Illustrative Proline Analog Compounds of Formula III(b) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 6
Compound No.: R1 R2
FAA ((a) and (b))
FAB ((a) and (b))
FAC ((a) and (b))
FAD ((a) and (b))
FAE ((a) and (b))
FAF ((a) and (b))
FAG ((a) and (b))
FAH ((a) and (b))
FAI ((a) and (b))
FAJ ((a) and (b))
FAK ((a) and (b))
FAL ((a) and (b))
FAM ((a) and (b))
FAN ((a) and (b))
FAO ((a) and (b))
FAP ((a) and (b))
FAQ ((a) and (b))
FAR ((a) and (b))
FAS ((a) and (b))
FAT ((a) and (b))
FAU ((a) and (b))
FAV ((a) and (b))
FAW ((a) and (b))
FAX ((a) and (b))
FAY ((a) and (b))
FAZ ((a) and (b))
FBA ((a) and (b))
FBB ((a) and (b))
FBC ((a) and (b))
FBD ((a) and (b))
FBE ((a) and (b))
FBF ((a) and (b))
FBG ((a) and (b))
FBH ((a) and (b))
FBI ((a) and (b))
FBJ ((a) and (b))

Additional, illustrative Proline Analog Compounds of Formula X include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R9 and R2 are as follows:

TABLE 7
Compound No.: R9 R2
GAA ((a) and (b))
GAB ((a) and (b))
GAC ((a) and (b))
GAD ((a) and (b))
GAE ((a) and (b))
GAF ((a) and (b))
GAG ((a) and (b))
GAH ((a) and (b))
GAI ((a) and (b))
GAJ ((a) and (b))
GAK ((a) and (b))
GAL ((a) and (b))
GAM ((a) and (b))
GAN ((a) and (b))
GAO ((a) and (b))
GAP ((a) and (b))
GAQ ((a) and (b))
GAR ((a) and (b))
GAS ((a) and (b))
GAT ((a) and (b))
GAU ((a) and (b))
GAV ((a) and (b))
GAW ((a) and (b))
GAX ((a) and (b))
GAY ((a) and (b))
GAZ ((a) and (b))
GBA ((a) and (b))
GBB ((a) and (b))
GBC ((a) and (b))
GBD ((a) and (b))
GBE ((a) and (b))

Additional, illustrative Proline Analog Compounds of Formula I(a) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 8
Compound No.: R1 R2
HAA ((a) and (b))
HAB ((a) and (b))
HAC ((a) and (b))
HAD ((a) and (b))
HAE ((a) and (b))
HAF ((a) and (b))
HAG ((a) and (b))
HAH ((a) and (b))
HAI ((a) and (b))
HAJ ((a) and (b))
HAK ((a) and (b))
HAL ((a) and (b))
HAM ((a) and (b))
HAN ((a) and (b))
HAO ((a) and (b))
HAP ((a) and (b))
HAQ ((a) and (b))
HAR ((a) and (b))
HAS ((a) and (b))
HAT ((a) and (b))
HAU ((a) and (b))
HAV ((a) and (b))
HAW ((a) and (b))
HAX ((a) and (b))
HAY ((a) and (b))
HAZ ((a) and (b))
HBA ((a) and (b))
HBB ((a) and (b))
HBC ((a) and (b))
HBD ((a) and (b))
HBE ((a) and (b))
HBF ((a) and (b))
HBG ((a) and (b))
HBH ((a) and (b))
HBI ((a) and (b))
HBJ ((a) and (b))

Illustrative Proline Analog Compounds of Formula I(b) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 9
Compound No.: R1 R2
IAA ((a) and (b))
IAB ((a) and (b))
IAC ((a) and (b))
IAD ((a) and (b))
IAE ((a) and (b))
IAF ((a) and (b))
IAG ((a) and (b))
IAH ((a) and (b))
IAI ((a) and (b))
IAJ ((a) and (b))
IAK ((a) and (b))
IAL ((a) and (b))
IAM ((a) and (b))
IAN ((a) and (b))
IAO ((a) and (b))
IAP ((a) and (b))
IAQ ((a) and (b))
IAR ((a) and (b))
IAS ((a) and (b))
IAT ((a) and (b))
IAU ((a) and (b))
IAV ((a) and (b))
IAW ((a) and (b))
IAX ((a) and (b))
IAY ((a) and (b))
IAZ ((a) and (b))
IBA ((a) and (b))
IBB ((a) and (b))
IBC ((a) and (b))
IBD ((a) and (b))
IBE ((a) and (b))
IBF ((a) and (b))
IBG ((a) and (b))
IBH ((a) and (b))
IBI ((a) and (b))
IBJ ((a) and (b))

Additional, illustrative Proline Analog Compounds of Formula II(a) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 10
Compound No.: R1 R2
JAA ((a) and (b))
JAB ((a) and (b))
JAC ((a) and (b))
JAD ((a) and (b))
JAE ((a) and (b))
JAF ((a) and (b))
JAG ((a) and (b))
JAH ((a) and (b))
JAI ((a) and (b))
JAJ ((a) and (b))
JAK ((a) and (b))
JAL ((a) and (b))
JAM ((a) and (b))
JAN ((a) and (b))
JAO ((a) and (b))
JAP ((a) and (b))
JAQ ((a) and (b))
JAR ((a) and (b))
JAS ((a) and (b))
JAT ((a) and (b))
JAU ((a) and (b))
JAV ((a) and (b))
JAW ((a) and (b))
JAX ((a) and (b))
JAY ((a) and (b))
JAZ ((a) and (b))
JBA ((a) and (b))
JBB ((a) and (b))
JBC ((a) and (b))
JBD ((a) and (b))
JBE ((a) and (b))
JBF ((a) and (b))
JBG ((a) and (b))
JBH ((a) and (b))
JBI ((a) and (b))
JBJ ((a) and (b))

Illustrative Proline Analog Compounds of Formula III(b) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 11
Compound No.: R1 R2
KAA ((a) and (b))
KAB ((a) and (b))
KAC ((a) and (b))
KAD ((a) and (b))
KAE ((a) and (b))
KAF ((a) and (b))
KAG ((a) and (b))
KAH ((a) and (b))
KAI ((a) and (b))
KAJ ((a) and (b))
KAK ((a) and (b))
KAL ((a) and (b))
KAM ((a) and (b))
KAN ((a) and (b))
KAO ((a) and (b))
KAP ((a) and (b))
KAQ ((a) and (b))
KAR ((a) and (b))
KAS ((a) and (b))
KAT ((a) and (b))
KAU ((a) and (b))
KAV ((a) and (b))
KAW ((a) and (b))
KAX ((a) and (b))
KAY ((a) and (b))
KAZ ((a) and (b))
KBA ((a) and (b))
KBB ((a) and (b))
KBC ((a) and (b))
KBD ((a) and (b))
KBE ((a) and (b))
KBF ((a) and (b))
KBG ((a) and (b))
KBH ((a) and (b))
KBI ((a) and (b))
KBJ ((a) and (b))

Illustrative Proline Analog Compounds of Formula I(a) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 12
Compound No.: R1 R2
LAA ((a) and (b))
LAB ((a) and (b))
LAC ((a) and (b))
LAD ((a) and (b))
LAE ((a) and (b))
LAF ((a) and (b))
LAG ((a) and (b))
LAH ((a) and (b))
LAI ((a) and (b))
LAJ ((a) and (b))
LAK ((a) and (b))
LAL ((a) and (b))
LAM ((a) and (b))
LAN ((a) and (b))
LAO ((a) and (b))
LAP ((a) and (b))
LAQ ((a) and (b))
LAR ((a) and (b))
LAS ((a) and (b))
LAT ((a) and (b))
LAU ((a) and (b))
LAV ((a) and (b))
LAW ((a) and (b))
LAX ((a) and (b))
LAY ((a) and (b))
LAZ ((a) and (b))
LBA ((a) and (b))
LBB ((a) and (b))
LBC ((a) and (b))
LBD ((a) and (b))
LBE ((a) and (b))
LBF ((a) and (b))
LBG ((a) and (b))
LBH ((a) and (b))
LBI ((a) and (b))
LBJ ((a) and (b))

Additional, illustrative Proline Analog Compounds of Formula I(b) include compounds of structure (a) and compounds of structure (b), below, as well as pharmaceutically-acceptable salts and solvates thereof:


wherein R1 and R2 are as follows:

TABLE 13
Compound No.: R1 R2
MAA ((a) and (b))
MAB ((a) and (b))
MAC ((a) and (b))
MAD ((a) and (b))
MAE ((a) and (b))
MAF ((a) and (b))
MAG ((a) and (b))
MAH ((a) and (b))
MAI ((a) and (b))
MAJ ((a) and (b))
MAK ((a) and (b))
MAL ((a) and (b))
MAM ((a) and (b))
MAN ((a) and (b))
MAO ((a) and (b))
MAP ((a) and (b))
MAQ ((a) and (b))
MAR ((a) and (b))
MAS ((a) and (b))
MAT ((a) and (b))
MAU ((a) and (b))
MAV ((a) and (b))
MAW ((a) and (b))
MAX ((a) and (b))
MAY ((a) and (b))
MAZ ((a) and (b))
MBA ((a) and (b))
MBB ((a) and (b))
MBC ((a) and (b))